THE NMDA ANTAGONIST MEMANTINE BLOCKS THE EXPRESSION AND MAINTENANCE OF MORPHINE-DEPENDENCE

The ability of memantine (1-amino-3,5-dimethyladamantane) to block the expression and maintenance of morphine dependence was examined in mic e. When administered to morphine-dependent mice 45 min prior to naloxo ne challenge, memantine (7.5-30 mg/kg IP) in a dose-dependent manner r educed jumping behavior (a manifestation of the expression of dependen ce). The ability of memantine to attenuate naloxone-precipitated jumpi ng was reversed by administration of glycine, an observation consisten t with electrophysiological studies indicating that memantine is a use -dependent (uncompetitive) N-methyl-D-aspartate (NMDA) antagonist. In an independent series of experiments, the effect of memantine on a pre established morphine dependence was investigated. A residual dependenc e to morphine was present 3 days after cessation of morphine administr ation. Repeated administration of memantine (10 mg/kg, IP) or the comp etitive NMDA antagonist NPC 17742 (2-amino-4,5-(1,2-cyclohexyl)-7-phos phonoheptanoic acid)] (6 mg/kg, IP) during this 3-day period abolished subsequent naloxone-precipitated jumping. In contrast, when administe red concurrently with morphine after dependence had already been well established, memantine (10 and 20 mg/kg, IP) did not affect the mainte nance of morphine dependence. Based on these findings, NMDA antagonist s appear to inhibit the maintenance of opioid dependence, an action di stinct from their acute inhibitory effects on the expression of depend ence. Nonetheless, these regimen-dependent effects of memantine indica te that the most efficacious use of NMDA antagonists would be in detox ified subjects, rather than in individuals with an established depende nce who are currently abusing opioids.